New insights into the genetic etiology of Alzheimer’s disease and related dementias – Nature.com

April 9, 2022 medical

Universit de Lille, INSERM, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE, Facteurs de risque et dterminants molculaires des maladies lies au vieillissement, Lille, France

Cline Bellenguez,Benjamin Grenier-Boley,Vincent Damotte,Marcos R. Costa,Julien Chapuis,R. Pineda-Snchez,Nathalie Fievet,Hieab Adams,Philippe Amouyel&Jean-Charles Lambert

Complex Genetics of Alzheimers Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Fahri Kkali,Christine Van Broeckhoven,Jasper Van Dongen&Kristel Sleegers

Laboratory of Neurogenetics, Institute Born - Bunge, Antwerp, Belgium

Fahri Kkali,Christine Van Broeckhoven,Jasper Van Dongen&Kristel Sleegers

Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

Fahri Kkali,Jasper Van Dongen&Kristel Sleegers

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands

Iris E. Jansen,Sven J. van der Lee,Henne Holstege,Marc Hulsman,Yolande A. L. Pijnenburg,Philip Scheltens,Niccolo Tes&Wiesje M. van der Flier

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, the Netherlands

Iris E. Jansen,Danielle Posthuma&Tim Lu

Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany

Luca Kleineidam,Victor Andrade,Michael T. Heneka,Wolfgang Maier,Anja Schneider,Michael Wagner,Kayenat Parveen,Frank Jessen&Alfredo Ramirez

Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany

Luca Kleineidam,Rafael Campos-Martin,Victor Andrade,Maria Carolina Dalmasso,Klaus Fliebach&Alfredo Ramirez

German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany

Luca Kleineidam,Klaus Fliebach,Michael T. Heneka,Wolfgang Maier,Matthias Schmid,Anja Schneider,Annika Spottke,Michael Wagner,Henning Boecker,Andr Lacour,Christine Herold,Tim Becker,Ying Wu,Yanbing Wang,Frank Jessen&Alfredo Ramirez

Research Center and Memory Clinic Fundaci ACE, Institut Catal de Neurocincies Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain

Sonia Moreno-Grau,Itziar de Rojas,Pablo Garcia-Gonzalez,Carla Abdelnour,Emilio Alarcn-Martn,Montserrat Alegret,Merc Boada,Miguel Calero,Ana Espinosa,Pablo Garca-Gonzlez,Isabel Hernndez,Marta Marqui,Laura Montrreal,Adelina Orellana,Gemma Ortega,Alba Prez-Cordn,Raquel Puerta,Natalia Roberto,Maite Rosende-Roca,ngela Sanabria,Oscar Sotolongo-Grau,Juan Pablo Tartan,Llus Trraga,Sergi Valero,Ana Maulen,Ana Pancho,Anna Gailhajenet,Asuncin Lafuente,Elvira Martn,Esther Pelej,Liliana Vargas,Mar Buendia,Marina Guitart,Mariona Moreno,Marta Ibarria,Nuria Aguilera,Pilar Caabate,Silvia Preckler,Susana Diego,Nuria Aguilera,Amanda Cano,Pilar Caabate,Ral Nuez-Llaves,Cludia Oliv,Ester Pelej&Agustn Ruiz

CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain

Sonia Moreno-Grau,Itziar de Rojas,Pablo Garcia-Gonzalez,Carla Abdelnour,Daniel Alcolea,Montserrat Alegret,Rafael Blesa,Merc Boada,Dolores Buiza-Rueda,Laura Cervera-Carles,Ana Espinosa,Juan Fortea,Mara J. Bullido,Ana Frank-Garca,Jose Maria Garca-Alberca,Isabel Hernndez,Carmen Lage,Alberto Lle,Adolfo Lopez de Munain,Marta Marqui,Angel Martn Montes,Miguel Medina,Pablo Mir,Fermin Moreno,Adelina Orellana,Gemma Ortega,Jordi Prez-Tur,Alberto Rbano,Eloy Rodriguez-Rodriguez,Maite Rosende-Roca,ngela Sanabria,Pascual Snchez Juan,Llus Trraga,Sergi Valero,Miren Zulaica,Ad Adarmes-Gmez,D. Macias-Garca,F. Carrillo,Isabel Sastre Merln,L. Garrote-Espina,M. Carrion-Claro,Ma Labrador,Mt Perin,P. Gmez-Garre,R. Escuela,R. Vigo-Ortega,S. Jess,Nuria Aguilera,Pilar Caabate,Astrid D. Adarmes-Gmez,Ftima Carrillo,Mario Carrin-Claro,Roco Escuela,Lorena Garrote-Espina,Pilar Gmez-Garre,Silvia Jess,Miguel Angel Labrador Espinosa,Sara Lpez-Garca,Daniel Macias-Garca,Mara Teresa Perin-Tocino,Roco Pineda-Snchez,Isabel Sastre,Rosario Vigo-Ortega,Jordi Clarimon&Agustn Ruiz

Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands

Najaf Amin,Amber Yaqub,Ivana Prokic,Shahzad Ahmad,Hata Comic,Tavia Evans,Maria Knol,William Kremen,Gena Roshchupkin,Dina Vojinovic,Mohsen Ghanbari,M. Arfan Ikram&Cornelia M. van Duijn

Nuffield Department of Population Health, Oxford University, Oxford, UK

Najaf Amin&Cornelia M. van Duijn

Department of Biostatistics, Epidemiology, and Informatics, Penn Neurodegeneration Genomics Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Adam C. Naj,Jin Sha,Alessandra Chesi,Beth A. Dombroski,Jacob Haut,Pavel P. Kuksa,Chien-Yueh Lee,Edward B. Lee,Yuk Yee Leung,Mingyao Li,John Malamon,Liming Qu,John Q. Trojanowski,Otto Valladares&Vivianna M. Van Deerlin

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Adam C. Naj,Valentina Escott-Price,Pavel P. Kuksa,Chien-Yueh Lee,Otto Valladares,Li-San Wang,Yi Zhao&Gerard D. Schellenberg

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK

Peter A. Holmans,Catherine Bresner,Janet Harwood,Lauren Luckcuck,Rachel Marshall,Amy Williams,Charlene Thomas,Chloe Davies,William Nash,Kimberley Dowzell,Atahualpa Castillo Morales,Mateus Bernardo-Harrington,Julie Williams&Rebecca Sims

CEA, Centre National de Recherche en Gnomique Humaine, Universit Paris-Saclay, Evry, France

Anne Boland,Cline Besse,Delphine Daian,Bertrand Fin,Robert Olaso&Jean-Franois Deleuze

Section Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands

Sven J. van der Lee,Henne Holstege,Marc Hulsman,Yiyi Ma&Niccolo Tes

Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil

Marcos R. Costa&Mikko Hiltunen

Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

Teemu Kuulasmaa,Alexa Beiser,Anita DeStefano,Kathryn L. Lunetta,Gina Peloso,Ruiqi Wang,Neil W. Kowall,Ann C. McKee,Jesse Mez,Robert A. Stern&Lindsay A. Farrer

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

Qiong Yang,Anita DeStefano,Lena Kilander,Malin Lwemark,Claudia L. Satizabal,Ruiqi Wang,Adrienne L. Cupples,Jose Dupuis,Shuo Li,Xuan Liu&Sudha Seshadri

Framingham Heart Study, Framingham, MA, USA

Qiong Yang,Oscar Lopez&Bruce M. Psaty

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

Joshua C. Bis&Alison E. Fohner

LACDR, Leiden, the Netherlands

Shahzad Ahmad

Department of Public Health and Carins Sciences/Geriatrics, Uppsala University, Uppsala, Sweden

Vilmantas Giedraitis&Martin Ingelsson

Centre of Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

Dag Aarsland

Institute of Psychiatry, Psychology & Neuroscience, London, UK

Dag Aarsland

Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Mlaga, Mlaga, Spain

Emilio Alarcn-Martn

Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autnoma de Barcelona, Barcelona, Spain

Daniel Alcolea,Rafael Blesa,Laura Cervera-Carles,Juan Fortea,Alberto Lle,Martin Rossor&Jordi Clarimon

Fundaci Docncia i Recerca MtuaTerrassa and Movement Disorders Unit, Department of Neurology, University Hospital MtuaTerrassa, Terrassa, Spain

Ignacio Alvarez,Mnica Diez-Fairen&Pau Pastor

Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain

Ignacio Alvarez,Mnica Diez-Fairen&Pau Pastor

Laboratorio de Gentica, Hospital Universitario Central de Asturias, Oviedo, Spain

Victoria lvarez&Irene Rosas Allende

Servicio de Neurologa, Hospital Universitario Central de Asturias- Oviedo and Instituto de Investigacin Biosanitaria del Principado de Asturias, Oviedo, Spain

Victoria lvarez,Carmen Martnez Rodrguez,Manuel Menndez-Gonzlez&Irene Rosas Allende

Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

Nicola J. Armstrong,Henry Brodaty,Anbupalam Thalamuthu,Perminder Sachdev&Karen Mather

First Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

Anthoula Tsolaki,Tegos Thomas,Anna Anastasiou&Magda Tsolaki

Alzheimer Hellas, Thessaloniki, Greece

Anthoula Tsolaki,Tegos Thomas&Magda Tsolaki

Unidad de Demencias, Hospital Clnico Universitario Virgen de la Arrixaca, Murcia, Spain

Carmen Antnez,Martirio Antequera,Agustina Legaz,Juan Marn-Muoz,Begoa Martnez,Victoriana Martnez,Maria Pilar Vicente&Liliana Vivancos

School of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy

Ildebrando Appollonio,Elisa Conti,Lucio Tremolizzo,Carlo Ferrarese,Simona Andreoni,Gessica Sala&Chiara Paola Zoia

Neurology Unit, San Gerardo Hospital, Monza, Italy

Ildebrando Appollonio,Lucio Tremolizzo&Carlo Ferrarese

Fondazione IRCCS CaGranda, Ospedale Policlinico, Milan, Italy

Marina Arcaro,Daniela Galimberti&Elio Scarpini

Department of Laboratory Diagnostics, III Laboratory of Analysis, Brescia Hospital, Brescia, Italy

Silvana Archetti

Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain

Alfonso Arias Pastor,Raquel Huerto Vilas&Gerard Piol-Ripoll

Institut de Recerca Biomedica de Lleida (IRBLLeida), Lleida, Spain

Alfonso Arias Pastor,Raquel Huerto Vilas&Gerard Piol-Ripoll

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Beatrice Arosio

Geriatic Unit, Fondazione C Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

Beatrice Arosio,Simona Ciccone,Paolo Dionigi Rossi&Evelyn Ferri

NORMENT Centre, University of Oslo, Oslo, Norway

Lavinia Athanasiu,Srdjan Djurovic,Alexey A. Shadrin,Shahram Bahrami&Ole A. Andreassen

EA 4468, Universit de Paris, APHP, Hpital Broca, Paris, France

Henri Bailly,Emmanuelle Duron,Olivier Hanon&Jean-Sbastien Vidal

Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy

Nerisa Banaj,Gianfranco Spalletta,Francesca Assogna,Fabrizio Piras,Federica Piras,Valentina Ciullo,Jacob Shofany&Yi Zhao

Servei de Neurologia, Hospital Universitari i Politcnic La Fe, Valencia, Spain

Miquel Baquero&Juan Andrs Burguera

Taub Institute on Alzheimers Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA

Sandra Barral,Richard Mayeux,Nikolaos Scarmeas,Giuseppe Tosto,Badri N. Vardarajan,Sandra Barral,Lawrence S. Honig,Scott Small,Jean-Paul Vonsattel&Jennifer Williamson

Excerpt from:
New insights into the genetic etiology of Alzheimer's disease and related dementias - Nature.com

Genetics

Study reveals a genetic overlap between childhood and adult mental health disorders – News-Medical.Net

April 9, 2022 medical

Hereditary factors are partly responsible for childhood anxiety and depression that persists into adulthood, according to University of Queensland researchers.

In the largest study of its kind in the world, the genetics of 64,641 children, aged between 3 and 18 years, were analyzed using longitudinal data from the Early Genetics and Lifeforce Epidemiology consortium.

Professor Christel Middeldorp, who holds a co-joint appointment with the UQ Child Health Research Centre and Children's Health Queensland, said the study showed children who had similar levels of anxiety and depression were also alike genetically.

It also revealed a genetic overlap between childhood and adult mental health disorders when comparing the results in this childhood study with results of previous studies in adults.

These findings are important because they help identify people most at risk of symptoms continuing across the lifespan, so intense treatment can be provided where needed."

Professor Christel Middeldorp, UQ Child Health Research Centre and Children's Health Queensland

It's the first time researchers have conducted such a large-scale study examining the role of genetics in repeated measures of anxiety and depression in children.

Professor Middeldorp said genetic variants needed to be investigated because they increased the risk of recurrence and co-occurrence with other disorders.

"Mental health symptoms often come together, so those who experience anxiety or depression have a greater risk of disorders such as ADHD, aggressive behavior," she said.

"We found that this co-occurrence is also due to genetic variants" Professor Middeldorp said.

Genetics account for around 40 per cent of a person's risk of suffering anxiety and depression, with environmental factors accounting for the rest.

Professor Middeldorp said while everyone could feel anxious or depressed from time to time, some people were better able to adjust to life's circumstances.

"People with an anxiety disorder ruminate about their situation, preventing them from moving on," she said.

"There is a difference in how people respond to stressors, and part of that difference is genetic."

Researchers will now analyze the interplay of genetics and environmental variables, such as school and family life, to see how together they influence childhood anxiety and depression.

Source:

Journal reference:

Jami, E.S., et al. (2022) Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms. Journal of the American Academy of Child and Adolescent Psychiatry. doi.org/10.1016/j.jaac.2021.11.035.

Original post:
Study reveals a genetic overlap between childhood and adult mental health disorders - News-Medical.Net

Genetics

European Society of Cardiology publishes new genetic testing guidelines for heart conditions – Cardiovascular Business

April 9, 2022 medical

In general, the authors write, cardiovascular disorders fall into broad categories: Mendelian cardiovascular disorders, caused by the inheritance of just one or two genetic variants, and disorders with complex inheritance, with multiple genetic variants that are potentially contributing factors.

In both categories, environmental and other non-genetic factors also contribute to the ultimate phenotypic expression, according to the document. However, Mendelian disorders often cluster in families, which may indicate an increased tilt toward family member screening in certain cases.

In Mendelian cardiovascular disorders with potentially devastating initial manifestations, such as SCD or aortic dissection, appropriate and prompt identification of individuals at risk is imperative, the authors wrote. Such clinical genetic testing for these single-gene disorders has been shown to be cost-effective and can be considered a success story in the application of genetics into clinical practice.

Before genetic testing is performed, the authors recommend genetic counseling for family members to inform them about the potentially life-changing consequences of a positive diagnosis.

For instance, if an individual has no symptoms but his or her sibling has a serious inherited cardiac disease, the first question should be do you want to know whether you have this condition, yes or no? Wilde said in the ESC statement. A diagnosis may trigger difficulties with insurance, getting a mortgage, and so on. He or she needs to be informed before making any decisions.

Of course, any decision should also take into consideration the potential benefits for patients and their families, both now and in the future. Noting the continued progress being made in gene therapy, the authors foresee a future where clinical applications may evolve even further with further research.

Looking to the future, with the advances being made in the field of gene therapy, the identification of the patients fundamental disease-causative substrate may enable not only genotype-guided therapies but also gene-specific, even pathogenic variant-specific therapies.

Combinedgenetic testing for cardiomyopathies and arrhythmias yields positive results

What cardiologists know, and dont know, about genetic testing for heart disease

Cardiologists identify 162 genes responsible for coronary heart disease

The rest is here:
European Society of Cardiology publishes new genetic testing guidelines for heart conditions - Cardiovascular Business

Genetics

Genetics of osteopontin in patients with chronic kidney disease: The German chronic kidney disease study – DocWire News

April 9, 2022 medical

This article was originally published here

PLoS Genet. 2022 Apr 6;18(4):e1010139. doi: 10.1371/journal.pgen.1010139. Online ahead of print.

ABSTRACT

Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

PMID:35385482 | DOI:10.1371/journal.pgen.1010139

Physiology

State agencies, AAA offer first Advanced Drug-Impairment Assessment through physiology and toxicology course – The Mountain Press

March 29, 2022 medical

TENNESSEE On March 7-8, the Tennessee Highway Safety Office partnered with the Tennessee Bureau of Investigation, Middle Tennessee State Universitys Forensic Science Laboratory, and AAA to offer the very first, Advanced Drug-Impairment Assessment through Physiology and Toxicology (ADAPT) course in the country.

The ADAPT course is designed to further the knowledge of law enforcement Drug Recognition Experts (DREs) regarding the effects of legal and illegal substances on the human body and driver impairment after consumption. Those who complete the course become better equipped to serve as expert court witnesses by offering stronger testimonies during the prosecution of impaired drivers. Currently, the Tennessee Highway Safety Office has certified 270 law enforcement officers as DREs in Tennessee, while training approximately 40 new DREs each year.

The THSO is proud to offer this training to help reduce impaired driving across Tennessee roadways, said THSO Director Buddy Lewis. We appreciate the TBI, MTSU, and AAA for their partnership in educating officers to save lives and protect our communities.

The class of 94 students consisted of representatives from 16 municipal law enforcement agencies, six county agencies, and the Tennessee Highway Patrol. Presenters included the Tennessee District Attorneys General Conference, Tennessee Traffic Safety Resource Prosecutors, the TBI, and the THSO.

Course training modules featured Joe Abrusci, Eastern Region DRE Coordinator for the International Association of Chiefs of Police; MTSU Assistant Professor Dr. Kiel Ormerod; and several TBI toxicologists including Melinda Quinn and JaQueya Ogilvie.

Modules included the following topics: Anatomy and Physiology of the Brain, CNS Depressants, CNS Stimulants, Pharmacology and Effects of THC in Marijuana, Hallucinogens and Dissociative Drugs, Esoteric Drugs and Emerging Drug Trends, Oral Fluid Testing, and Working with DREs in Court.

Physiology

Yale Researchers Continue to Unravel the Mystery of Metformin – Yale School of Medicine

March 29, 2022 medical

Yale researchers have further elucidated the mechanism of metformin, a widely used type 2 diabetes medication that, despite its long history of being safe and effective, works in a way that has remained elusive to scientists.

On March 1, Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, published his labs findings on how metformin works to suppress gluconeogenesis through inhibiting Complex IV activity. Now, a different study led by Yingqun Huang, MD, PhD, professor of obstetrics, gynecology & reproductive sciences, builds upon Shulmans findings and further illuminates how the drug works. Her team published its findings in Proceedings of the National Academy of Sciences on March 28. Our research not only discovered a new mechanism of metformin, but also identified potential therapeutic molecular targets, says Huang.

Shulmans findings over recent years supporting an oxidation-reduction (redox)-dependent mechanism of metforminin which cytosolic redox is increasedintrigued Huangs lab. But while Shulmans lab has focused on how inhibition of the mitochondrial enzyme Complex IV promotes an increased cytosolic redox state and inhibition of gluconeogenesis [glucose production from glycerol, lactate and amino acids], Huang is interested in how increased redox changes hepatocytes [liver cells] further downstreama mechanism researchers are now debating.

In 2020, Huangs lab published a paper in Nature Communications that found that the expression of a gene known as TET3 was increased in mice and humans with diabetes. In turn, the expression of a specific fetal isoform of the HNF4A gene was also increased. In healthy adult livers, the adult form of HNF4A is predominantly expressed. In patients with diabetes, however, the fetal isoform is chronically increased because TET3 is also chronically increased. This fetal isoform also increases gluconeogenesis by regulating key enzymes involved in the process.

In our published paper two years ago, we identified that the upregulation of TET3 and the HNF4A fetal isoform in humans and mice with diabetes contribute to unabated gluconeogenesis in the liver, says Da Li, professor at China Medical University and co-author on both studies. Now, through its latest work, Huangs lab has discovered that when metformin induces an increase in cellular redox, this in turn increases let-7, a small microRNA molecule. When let-7 increases, it binds to and downregulates TET3, suppressing the HNF4A fetal isoform and also gluconeogenesis mproving diabetes

In the livers of diabetes, let-7 is depressed, explains Di Xie, associate research scientist in Huangs lab and first author of the study. Metformin brings let-7 back to normal levels and inhibits gluconeogenesis.

Unabated glucose production from the liver is one of the key mechanisms of diabetes. Through better understanding how metformin works to suppress gluconeogenesis, Huang hopes her work will lead to more effective drugs with fewer side effects. The study also identified potential therapeutic targets including let-7. Scientists could potentially use a vector such as a mild virus known as adeno-associated virus, for example, to specifically deliver a let-7 mimic to the liver of patients with diabetes to enhance let-7 expression and treat the condition. Huang hopes to develop such a vector for delivering therapeutics like a let-7 mimic in future research.

Physiology

Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular…

March 29, 2022 medical

This article was originally published here

Heart. 2022 Mar 22:heartjnl-2021-320718. doi: 10.1136/heartjnl-2021-320718. Online ahead of print.

ABSTRACT

Nearly half of all patients with angina have non-obstructive coronary artery disease (ANOCA); this is an umbrella term comprising heterogeneous vascular disorders, each with disparate pathophysiology and prognosis. Approximately two-thirds of patients with ANOCA have coronary microvascular disease (CMD). CMD can be secondary to architectural changes within the microcirculation or secondary to vasomotor dysfunction. An inability of the coronary vasculature to augment blood flow in response to heightened myocardial demand is defined as an impaired coronary flow reserve (CFR), which can be measured non-invasively, using imaging, or invasively during cardiac catheterisation. Impaired CFR is associated with myocardial ischaemia and adverse cardiovascular outcomes.The CMD workstream is part of the cardiovascular partnership between the British Heart Foundation and The National Institute for Health Research in the UK and comprises specialist cardiac centres with expertise in coronary physiology assessment. This document outlines the two main modalities (thermodilution and Doppler techniques) for estimation of coronary flow, vasomotor testing using acetylcholine, and outlines a standard operating procedure that could be considered for adoption by national networks. Accurate and timely disease characterisation of patients with ANOCA will enable clinicians to tailor therapy according to their patients coronary physiology. This has been shown to improve patients quality of life and may lead to improved cardiovascular outcomes in the long term.

PMID:35318254 | DOI:10.1136/heartjnl-2021-320718

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Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular...

Physiology

How organisms have adapted to the passage of time and other unsolved questions about the many-faceted mystery of time – EurekAlert

March 29, 2022 medical

image:13th Symposium Behind and Beyond the Brain" view more

Credit: BIAL Foundation

What are the biological signatures of time? In the session on The Biology of Time, on April 8th, experts on psychology of time, neurophysiology, circadian biology and neural coding will discuss how time influences biological architectures, perceptual encoding and prediction of physical relations and social cognition.

Under the theme The mystery of time, the 13th Symposium of the BIAL Foundation gathers some of the most prominent scientists and philosophers to engage in an interdisciplinary dialogue around the many aspects of time.

The second session, taking place on the morning of April 8th, is aimed at surveying the biology of time. Moderated by Miguel Castelo-Branco (Coimbra, PT), it features lectures by Julia Mossbridge (San Diego and Petaluma, USA), Michael Brecht (Berlin, DE), and Joseph S. Takahashi (Dallas, USA), who will examine how organisms have adapted to the passage of time: from biological clocks to the mechanisms of memory, from pre-sponding to circadian rhythms, the speakers will explore the many ways in which neural systems respond to time in the absence of specific receptors systems dedicated to perceive it.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist known for having discovered the genetic basis for the mammalian circadian clock in 1994 and also for having identified the Clock gene in 1997. In this session, Takahashi will focus on circadian clocks and their impact on metabolism, aging and longevity. His lecture will discuss recent discoveries on the neuronal network in the suprachiasmatic nucleus.

In addition to controlling the timing of behavior and physiology, the clock gene network interacts directly with many other pathways in the cell. These include metabolism, immune function, cardiovascular function and cell growth to name a few. Regarding the current diet trend known as intermittent fasting, Takahashi says that with respect to metabolism, the timing of nutrient consumption is crucial, and we and others have shown that restricting the timing of feeding has many health benefits, being a critical factor for aging and longevity.

The morning will close with a keynote lecture by Wolf Singer (Frankfurt, DE), who will overview what sorts of mechanisms have evolved to make it possible for living things to be able to parse time. Among many other questions, the apparent paradox will be discussed that the perception of elapsed and remembered time is strongly dependent on context while the reproduction of temporally structured sequences can be extremely precise.

The Symposium Behind and Beyond the Brain will be held from April 6 to 9, 2022, at Casa do Mdico, Porto, Portugal. The event will be organised in a hybrid format involving both in-person and virtual participants to be accessible to a wider audience. Registrations are open and available here.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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How organisms have adapted to the passage of time and other unsolved questions about the many-faceted mystery of time - EurekAlert

Physiology

How the gut communicates with the brain – EurekAlert

March 29, 2022 medical

How the gut communicates with the brain

How the second brain the enteric nervous system in our gut communicates with our first brain has been one of the most challenging questions faced by enteric neuroscientists, until now.

New research from Flinders University has discovered how specialised cells within the gut can communicate with both the brain and spinal cord, which up until now had remained a major mystery.

The gut-brain axis consists of bidirectional communication between the brain and the gut, which links emotional and cognitive centres of the brain with peripheral intestinal functions, says study author Professor Nick Spencer from the College of Medicine and Public Health.

Recent advances in research have described the importance of gut microbiota in influencing these pathways but we had yet to uncover how the communication was working.

The study, published in the American Journal of Physiology, reveals a breakthrough discovery regarding how enterochromaffin cells communicate with sensory nerve endings.

Within the gut wall lie specialised cells called enterochromaffin (EC) cells that produce and release hormones and neurotransmitters in response to particular stimuli that are ingested when we eat, says Professor Spencer.

These EC cells release the vast majority of serotonin into the body, so our study has uncovered a major clue into how the food we eat stimulates the release of serotonin, which then acts on the nerves to communicate with the brain.

There is a direct connection between serotonin levels in our body and depression and how we feel. So, understanding how the gut EC cells communicate with the brain is of major importance.

The team made the discovery using a neuronal tracing technique developed in their lab, not used anywhere else in the world, allowing them to see the sensory nerve endings with clarity, for the first time, in the gut wall.

This has not been possible, until now, because there were so many other types of nerves also present in the gut its like finding a needle in a haystack, says Professor Spencer.

The technique allowed the researchers to see that EC cells likely release substances by a process of diffusion, which then acts on the sensory nerves that communicate with the brain.

No direct physical connection between the EC cells and sensory nerve endings were found, contrary to some suggestions.

The gut is the only organ with its own nervous system, known as the Enteric Nervous System or the second brain. We now have a better understanding of how the second brain communicates with the first brain, says Professor Spencer.

The article The gut-brain axis: spatial relationship between spinal afferent nerves and 5-HT-containing enterochromaffin cells in mucosa of mouse colon by Kelsi N. Dodds, Lee Travis, Melinda A. Kyloh, Lauren A. Jones, Damien J. Keating, and Nick J. Spencer is published in the American Journal of Physiology-Gastrointestinal and Liver Physiology. DOI: 10.1152/ajpgi.00019.2022.

The study was supported by the National Health and Medical Research Council and the Australian Research Council.

Observational study

Animals

The gut-brain axis: spatial relationship between spinal afferent nerves and 5-HT-containing enterochromaffin cells in mucosa of mouse colon

16-Mar-2022

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How the gut communicates with the brain - EurekAlert

Physiology

Opinion | Permanent Daylight Saving Time Is the Wrong Choice – Medpage Today

March 29, 2022 medical

Earlier this month, the Senate unanimously passed the Sunshine Protection Act. The legislation proposes making daylight saving time (DST) permanent in the U.S. One motivator is to stop the unpopular practice of switching back and forth from standard time (ST) to DST each year. The springtime switch from ST to DST is most annoying because we lose sleep to wake up an hour earlier. This "spring forward" is also associated with an increase in traffic accidents, cardiovascular events, and other health hazards.

Although there is strong support from the public and research communities for ending the biannual time changes, the question is, what's the best alternative: permanent ST or DST? Unfortunately, the Sunshine Protection Act mandates permanent DST. From the scientific and medical point of view, this is the worse alternative. The optimal choice is permanent standard time.

Why is permanent ST better for human health and wellbeing? We need a little background: Our 24-hour day is determined by the rotation of earth that leads to a day-night energetic cycle driven by the sun. Life on earth has evolved under this daily cycle for millennia, and virtually all living systems have internal 24-hour or "circadian" clocks that anticipate daily challenges such as food and shelter. Having our body clocks in tune with the sun clock aligns just about every aspect of our physiology and behavior. Humans synchronize to local time primarily by light. While ST was designed so the middle of each time zone has the sun directly overhead at noon, DST is a social and political construct that advances our social schedule by 1 hour without changing environmental light cycles. During permanent DST, increased exposure to evening light and decreased morning light exposure tells the circadian system to wake up later the next morning, misaligning our daily rhythms with local time and making it tougher to live without an alarm clock.

Even a 1-hour deviation creates a chronic internal desynchrony between our body clocks and the sun. Why would we go against the tuning of our body clock to the sun? Does it improve mental health? Does it decrease accidents? Does it save energy? Does it reduce crime? The answer to all of these is no.

Research over the last 25 years shows we have 24-hour biological rhythms that are generated by a set of genes that turn on and turn off once each day. Surprisingly, this research showed that this circadian clock is found in almost every cell in our bodies. This cellular circadian clock not only controls our daily behaviors, such as our sleep-wake and fasting-eating cycles, but also our metabolism, immune function, and cognitive ability. The circadian clocks in our bodies are normally aligned and kept in sync by the environmental day-night cycle. Until the advent of DST in 1916, the sun was the primary synchronizer of our circadian clocks. The normal alignment of our circadian clocks by the sun is in register with Standard Time. DST causes a 1-hour misalignment of our clocks with the natural day-night cycle. Permanent DST would lead to a permanent misalignment of our clocks with the solar day.

While a 1-hour misalignment may sound trivial, consider that there would be 75 to 100 more dark morning commutes during permanent DST compared to permanent ST. Many lines of evidence show significant consequences of circadian misalignment. Laboratory and field experiments in humans and rodents have shown that circadian misalignment can lead to cognitive impairment, mood dysregulation, a reduction in glucose regulation and insulin sensitivity, and changes in satiety hormones such as leptin that can lead to increased food consumption and weight gain.

Most concerning regarding permanent DST is epidemiological evidence showing a significant increase in the rates of cancers on the western border of each U.S. time zone compared to the eastern border. There is an overall 3 to 4% increase in cancer risk ratio for every 5 degrees west within a time zone, which is on average about 15 degrees in longitude. This was found in each of the four U.S. time zones. The border separating time zones is an arbitrary, politically drawn line, making it both surprising and notable that cancer rates can vary on either side of each time zone. This suggests the cause of this association with cancer is the greater circadian misalignment for those living on the western edge of their time zone.

Now the bad news: being on permanent DST is equivalent to being on the extreme western border of each time zone, suggesting this may increase cancer rates (as a consequence of permanent circadian misalignment). Studies also find increases in obesity and heart attacks on western edges of time zones. Congress must seriously consider these consequences of permanent DST.

Countering Permanent DST Proponents

Proponents of permanent DST argue that 1 hour more of light at the end of the day will enable people to have more time to enjoy sunshine after work. This is the "extend the day" argument. But extending the day by 1 hour of light in the evening can only occur at the expense of a loss of 1 hour of light in the morning. As a wise old quote goes, only a fool would believe you could cut a foot off the top of a blanket and sew it to the bottom and have a longer blanket. Some argue 1 hour of light in the evening is more valuable than 1 hour of dark in the morning -- they say businesses will have more customers, and there will be less crime and fewer traffic accidents at night. Thus, there is strong motivation and strong lobbies from retail and leisure businesses to adopt permanent DST. The evidence for improved public safety is, however, misrepresented and even contradicted by other studies.

Others, such as individuals with seasonal affective disorder (SAD) -- which is triggered by the short days of winter -- argue permanent DST is better because extra light in the evening makes them feel better. However, there is not an "extra" hour of light; rather that hour of light is moved in our social schedules from the morning to the evening. Research on bright light therapy for SAD has shown morning light is more effective in alleviating the symptoms of SAD than evening light. In addition, researchers find that light in the morning (e.g., during the commute to school or work) is associated with improved health, safety, and economics. In contrast, dark mornings and light afternoons (resulting from switching clocks to DST) is associated with poorer outcomes.

We should also pay attention to history -- this wouldn't be the first time we tried switch to permanent DST. In the 1970s, the U.S. adopted permanent DST in response to the oil embargo in order to save energy. It was reversed within a year primarily because of concerns when children, sadly, were killed waiting in the dark for their school buses. The idea of saving energy stems from "war time," which was adopted during World War I and II with the thought of saving energy and increasing productivity. However, in each of the cases when permanent DST was adopted, there was a cry to go back to standard time.

It turns out that people don't like permanent DST in the winter time. Sunrise will occur 1 hour later, and the afternoons will still be dark because of the short days of winter in northern latitudes. So, there is not much extra evening light in the winter because sunset occurs near the end of the work day. Thus, we predict most people will not be happy with DST in the winter, and history will likely repeat itself and we will again abolish DST.

Another fallacy of DST is that farmers like it. This is not true. Farmers generally dislike the current switching between ST and DST because farm animals (and in reality all animals) are not paying attention to our social time zones, but rather are waking and sleeping with the sun. Thus, animals are not going to switch to permanent DST because they will remain on solar time, and farmers (if we adopt DST) will be permanently misaligned with the natural cycles of their animals.

Finally, many medical organizations have endorsed permanent ST. None, to our knowledge, advocate for permanent DST. Therefore, for scientific and medical reasons, Congress should abolish switching to DST and adopt permanent standard time.

Joseph S. Takahashi, PhD, is an Investigator in the Howard Hughes Medical Institute in Chevy Chase, Maryland, and a member of the National Academy of Science and National Academy of Medicine, and recipient of the Gruber Neuroscience Prize. He is known for his discovery of the CLOCK gene in mice and humans, which led to the description of the circadian clock mechanism in mammals. Erik Herzog, PhD, is the Viktor Hamburger Distinguished Professor of Arts and Sciences at Washington University in St. Louis. His laboratory studies the molecules, cells, and circuits that underlie daily rhythms in physiology and behavior.

Disclosures

Takahashi is a co-founder and Science Advisory Board member of Synchronicity Pharma.

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Opinion | Permanent Daylight Saving Time Is the Wrong Choice - Medpage Today